Clinical Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome

Pulmonary Arterial Hypertension Clinical Trial

— MAESTRO  

Official title:

A Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase 3 Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01743001
• Other study ID #: AC-055-305
• Status: Completed
• Phase: Phase 3
• First received: November 29, 2012
• Last updated: February 22, 2018
• Start date: May 21, 2013
• Est. completion date: December 1, 2016

Study information

• Verified date: January 2018
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Clinical study to assess the efficacy, safety, and tolerability of macitentan in subjects with Eisenmenger Syndrome.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 226
• Est. completion date: December 1, 2016
• Est. primary completion date: December 1, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

• Subjects:

• not participating in the hemodynamic sub-study: males or females = 12 years of age.

• participating in the hemodynamic sub-study: males or females = 18 years of age.

• Subjects (including those with Down Syndrome [DS]) with confirmed Eisenmenger Syndrome [ES] (European Society of Cardiology [ESC] and the European Respiratory Society [ERS] guidelines):

1. Established by echocardiography as:

• Large congenital shunting defect at atrial, ventricular or arterial level*

• and right to left shunt or bi-directional shunt with prevalent right to left direction.

2. Resting peripheral oxygen saturation (SpO2) = 90% and > 70% (pulse oximetry, room air).

The lower limit is 65% if a subject is living at an altitude greater than 2500 m above sea level.

*Subjects with any of the following open defects are eligible for the study either as an isolated defect or in combination:

• atrial septal defect (ASD)

• ventricular septal defect (VSD)

• partial or complete atrioventricular septal defect (AVSD)

• patent ductus arteriosus (PDA)

• aortopulmonary window (AP window)

• total or partial anomalous pulmonary venous return (TAPVR, PAPVR) The defects may be either unoperated or previously palliated surgically (provided significant residual defect remains).

The Steering Committee will review the echocardiography data of all subjects (main study and sub study) to confirm eligibility prior to Randomization.

• Subjects with the following findings at cardiac catheterization:

• Mean resting pulmonary arterial pressure (mPAP) > 25 mmHg

• Pulmonary capillary wedge pressure (PCWP) or mean left atrial pressure (LAP) or left ventricular end diastolic pressure (LVED) = 15 mmHg

• Pulmonary vascular resistance (PVR) = 800 dyn·s/cm5 or = 10 Wood units

• Subjects with WHO functional class = II.

• Subjects able to reliably perform the the 6-minute walk test (6MWT) with a minimum distance of 50 m and a maximum distance of 450 m.

Exclusion Criteria:

• Main study and hemodynamic sub-study: Any of the following conditions previously known or identified via cardiac catheterization or echocardiography:

• Pulmonary arterial or venous stenosis > 25% size of native pulmonary artery (PA) or pulmonary vein

• Severe tricuspid regurgitation in the setting of left to right shunt at the ventricular or atrial level

• Greater than mild tricuspid stenosis

• Intracavitary RV outflow obstruction

• Greater than mild mitral stenosis

• Intracavitary LV outflow obstruction

• Subvalvular or supravalvular aortic stenosis

• Aortic coarctation

• Greater than moderate mitral regurgitation

• Recognized extracardiac systemic venous collaterals to the pulmonary venous circulation

• Recognized hepatic wedge pressure-inferior vena cava pressure gradient >12 mm Hg

• PCWP "v" waves >20 mmHg

• Tetralogy of Fallot

• Truncus arteriosus

• Interrupted aortic arch

• Transposition of great arteries

• Single ventricle defects: absent AV connection (mitral or tricuspid atresia), double inlet AV connections left or right ventricle, functional univentricular heart (unbalanced AVSD, hypoplastic RV, double outlet RV), hypoplastic left heart syndrome

• Ebstein's anomaly

• Severe aortic regurgitation

• Pulmonary atresia

• PAPVR or TAPVR, ONLY if there is lung hypoplasia or if documentation confirming the absence of lung hypoplasia does not exist.

For subjects participating in the hemodynamic sub-study the following will also be considered exclusion criteria:

• SVC stenosis >25% size of native vessel

• PDA, AP window, TAPVR, PAPVR, or ASD sinus venosus with anomalous pulmonary veins

• Down Syndrome

• Subjects with deterioration of their clinical status within 3 months prior to Screening or during the Screening period.

• Known moderate-to-severe restrictive (i.e., total lung capacity [TLC] < 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second [FEV1] < 80 % of predicted value, and with FEV1 / forced vital capacity [FVC] < 70%)

• Treatment with prostanoids within 1 month prior to Randomization

• Subjects who initiated a PDE-5 inhibitor within 1 month prior to Randomization or those on a PDE-5 inhibitor for whom the dose has not been stable within 1 month prior to Randomization

• Treatment with endothelin receptor antagonists (ERAs) within 1 month prior to Randomization

• Subjects who initiated diuretics within 1 week prior to Randomization or subjects whose diuretic treatment has not been stable for at least 1 week prior to Randomization

• Subjects being considered for an organ transplant

Related Conditions & MeSH terms

• Eisenmenger Complex
• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Macitentan 10 mg
Macitentan 10 mg oral tablet once daily
• Placebo
Macitentan-matching placebo oral tablet once daily

Locations

Country	Name	City	State
Austria	Gen Hosp Univ Vienna Dept Cardiology	Vienna
Bulgaria	Mhat Nat Card Hosp - Cardiology Clinic	Sofia
Bulgaria	Mhat Nat Card Hosp - Pediatric Clin / Ped Card Dept	Sofia
Bulgaria	Mhat Sveta Anna Clin Card	Sofia
Chile	Inst Nat Torax, Unidad Cardiopatia Congenitas Del Adulto	Providencia
Chile	Clinica Tabancura - Cardio Unit	Santiago
China	Beijing Anzhen Hospital, Cardiology Dpt	Beijing
China	Cardiovascular Institute&Fuwai Hospital	Beijing
China	Guangdong General Hospital, Cardiology Dpt	Guangzhou	Guangdong
China	Shanghai Pulmonary Hospital, Dept of Pulmonary Circulation	Shanghai
China	The General Hosp of Shenyang Military Region	Shenyang	Liaoning
China	Wu Han Asia Heart Hosp	Wuhan	Hubei
France	Hosp La Timone - Dept Pediatric Cardiology	Marseille Cedex 5
France	Hosp Laennec - Dept Cardiology	Nantes Cedex 1
France	Hosp Pompidou - Dept Congenital Cardiac Diseases	Paris Cedex 15
France	Hosp Cardiology Haut Leveque - Dept Congenital Diseases	Pessac
Germany	Herzzentrum Berlin, Ped Cardiology	Berlin
Germany	Universitätsklinikum Giessen - Pediatric Heart Center	Giessen
Germany	Uni Heidelberg - Kinderkardiologie	Heidelberg
Greece	Ahepa University General Hospital	Thessaloniki
Israel	Rabin Medical Centre - Pulmonology	Petach Tikvah
Malaysia	Institut Jantung Negara	Kuala Lumpur
Mexico	Instituto Nacional de Cardiologia (Inc) Ignacio Chavez	Mexico City
Mexico	Unidad de Investigacion Clin En Med, Sc (Udicem)	Monterrey	Nuevo Leon
Mexico	Instituto de Corazon de Querètaro	Querétaro
Philippines	PHC, MAB	Manila
Poland	Cardiology Gdansk Univ	Gdansk
Poland	Cardiology Kraków Univ	Krakow
Poland	Cardiology Wroclaw	Wroclaw
Portugal	Hosp Univ Coimbra - Dpt Cardiology	Coimbra
Portugal	Hosp Sta Marta - Dept Cardiology	Lisboa
Romania	Er Inst For Cardvasc Dis "Prof Dr Cc Iliescu" - Card Ii	Bucuresti
Romania	Cardio Med Srl	Targu-Mures
Romania	Clin Hosp For Inf and Pulm Dis Victor Babes - Ii Pulm	Timisoara
Russian Federation	Sci Institute Systemic Problems Cardio Diseases Kemerovo	Kemerovo
Russian Federation	Russian Cardiology Scientific and Production Complex	Moscow
Russian Federation	V. A. Almazov Institute of Cardiology	St Petersburg
Serbia	Clin Hosp Ctr Zemun - Cardiology Dept	Belgrade
Serbia	Dedinje Cardiovasc Inst - Cardiovasc Research Ctr	Belgrade
Serbia	Mother and Child Health Care Inst "Dr Vukan Cupic"	Belgrade
Spain	Hosp Univ Vall D'Hebron - Dpt Congenital Heart Disease Adult	Barcelona
Spain	Hosp Univ Virgen Macarena - Dpt Cardiology	Sevilla
Spain	Hosp Universitario La Fe Dpt Cardiology	Valencia
Turkey	Omu Pediatry	Samsun
United Kingdom	Bristol Univ Hosp Congenital Heart Centre	Bristol
United States	Emory University Hospital/the Emory Clinic	Atlanta	Georgia
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Texas Children'S Hosp - Dept of Cardiology	Houston	Texas
United States	Children'S Heart Center Nevada	Las Vegas	Nevada
United States	Ahmanson/UCLA Heart Disease Center	Los Angeles	California
United States	Stanford Hospital and Clinic	Palo Alto	California
United States	Barnes-Jewish Hosp/Wash Univ School of Med	Saint Louis	Missouri
Vietnam	Hanoi Medical University Hospital	Hanoi
Vietnam	Children's Hospital, Ho Chi Minh	Ho Chi Minh
Vietnam	Tam Duc Hospital	Ho Chi Minh

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Vietnam,  Austria,  Bulgaria,  Chile,  China,  France,  Germany,  Greece,  Israel,  Malaysia,  Mexico,  Philippines,  Poland,  Portugal,  Romania,  Russian Federation,  Serbia,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD)	The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.	From baseline to Week 16
Secondary	Change From Baseline to Week 16 in WHO Functional Class	A shift in WHO functional classes is considered an 'improvement' when shifting to a lower class (e.g. from class III to class II) or a 'worsening' when shifting to a higher class (e.g. from class III to class IV). Definition of functional classes as follows - Class I: no symptoms with exercise or at rest. Class II: No symptoms at rest but uncomfortable and short of breath with normal activity such as climbing a flight of stairs, grocery shopping, or making the bed. Class III: May not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting (e.g. doing normal chores around the house, have to take breaks while doing activities of daily living). Class IV: Symptoms at rest and severe symptoms with any activity. Most patients also have edema in the feet and ankles as result of right heart failure.	From baseline to Week 16
Secondary	Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index	This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 16 compared to baseline. The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement.	From baseline to Week 16
Secondary	Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire	The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of the functional health and well-being scores (i.e., physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), as well as psychometrically based physical and mental health summary measures and a preference-based health utility (health rated as much better now than one year ago to much worse now than one year ago). It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group.; For each of the domains and scores that the SF36 measures an aggregate percentage score is produced. The percentage scores range from 0% (lowest or worst possible level of functioning) to 100% (highest or best possible level of functioning). A higher score for the individual domains and summary component scores indicates a better condition of the subject.	From baseline to Week 16